Cancer remains a major health concern. Despite increased understanding of many aspects of cancer, the methods available for its treatment continue to have limited success. First of all, the number of cancer therapies is limited, and none provides an absolute guarantee of success. Second, there are many types of malignancies, and the success of a particular therapy for treating one type of cancer does not mean that it will be broadly applicable to other types. Third, many cancer treatments are associated with toxic side effects. Most treatments rely on an approach that involves killing off rapidly growing cells; however, these treatments are not specific to cancer cells and can adversely affect any dividing healthy cells. Fourth, assessing molecular changes associated with cancerous cells remains difficult. Given these limitations in the current arsenal of anti-cancer treatments, how can the best therapy for a given patient be designed? The ability to detect a malignancy as early as possible, and assess its severity, is extremely helpful in designing an effective therapeutic approach. Thus, methods for detecting the presence of malignant cells and understanding their disease state are desirable, and will contribute to our ability to tailor cancer treatment to a patient's disease.
While different forms of cancer have different properties, one factor which many cancers share is the ability to metastasize. Until such time as metastasis occurs, a tumor, although it may be malignant, is confined to one area of the body. This may cause discomfort and/or pain, or even lead to more serious problems including death, but if it can be located, it may be surgically removed and, if done with adequate care, be treatable. However, once metastasis sets in, cancerous cells have invaded the body and while surgical resection may remove the parent tumor, this does not address other tumors. Only chemotherapy, or some particular form of targeting therapy, then stands any chance of success.
The process of tumor metastasis is a multistage event involving local invasion and destruction of the intracellular matrix, intravasation into blood vessels, lymphatics or other channels of transport, survival in the circulation, extravasation out of the vessels in the secondary site(s), and growth in the new location(s) (Fidler, et al., Adv. Cancer Res. 28, 149-250 (1978), Liotta, et al., Cancer Treatment Res. 40, 223-238 (1988), Nicolson, Biochim. Biophy. Acta 948, 175-224 (1988) and Zetter, N. Eng. J. Med. 322, 605-612 (1990)). Success in establishing metastatic deposits requires tumor cells to be able to accomplish these steps sequentially. Common to many steps of the metastatic process is a requirement for motility. The enhanced movement of malignant tumor cells is a major contributor to the progression of the disease toward metastasis. Increased cell motility has been associated with enhanced metastatic potential in animal as well as human tumors (Hosaka, et al., Gann 69, 273-276 (1978) and Haemmerlin, et al., Int. J. Cancer 27, 603-610 (1981)).
Tumor angiogenesis is essential for both primary tumor expansion and metastatic tumor spread (Blood et al., Biochim. Biophys. Acta 1032:89-118 (1990)). Angiogenesis is a fundamental process by which new blood vessels are formed. Progressive tumor growth necessitates the continuous induction of new capillary blood vessels which converge upon the tumor. In addition, the presence of blood vessels within a tumor provides a ready route for malignant cells to enter the blood stream and initiate metastasis. Thus, malignancy is a systemic disease in which interactions between the neoplastic cells and their environment play a crucial role during evolution of the pathological process (Fidler, I. J., Cancer Metastasis Rev. 5:29-49 (1986)).
Identifying factors that are associated with tumor progression, particularly metastasis and angiogenesis, is clearly a prerequisite not only for a full understanding of cancer, but also for the development of rational new anti-cancer therapies. In addition to using such factors for diagnosis and prognosis, these factors represent important targets for identifying novel anti-cancer compounds, and are useful for identifying new modes of treatment, such as inhibition of metastasis. One difficulty, however, is that the genes characteristic of cancerous cells are very often host genes being abnormally expressed. For example, a protein marker for a given cancer, while expressed in high levels in connection with that cancer, may also be expressed elsewhere throughout the body, albeit at reduced levels. Thus, some care is required in determining whether the expression of any single gene in a given cancer is a meaningful marker for the progression of the disease.
Although progress has been made in the identification of various potential breast cancer marker genes, as well as other biomolecular markers of cancer (e.g., Prostate Specific Antigen in the case of Prostate cancer) there remains a continuing need for new marker genes along with their expressed proteins that can be used to specifically and selectively identify the appearance and pathogenic development of cancer in a patient.
PCT publication WO 00/58473 discloses a sequence of Clone 3003. Clone 3003 contains two identifiable domains one of which is a collagen triple helix. The PCT publication reports that Clone 3003 is expressed in thyroid, bone marrow and lymph node and is believed to have disease associations related to hyper- and hypoparathyroidism, hemophilia, hypercoagulation, idiopathic thrombocytopenia purpura, autoimmune diseases, allergies, immunodeficiencies, transplantation complications, graft versus host disease and lymphedema. The PCT publication WO 00/58473 does not teach or disclose an association of this clone to cancer.